The overall goal of this proposal is to elucidate the mechanisms by which chronic viral infection mediates telomere loss and T cell aging that may lead to vaccine failure, with an aim to develop effective means to improve vaccine efficacy in virally infected individuals. To this end, we will use a model of hepatitis B virus (HBV) vaccine responses in the setting of hepatitis C virus (HCV) infection. Due to shared risk factors and the prevalence of hepatitis B and hepatitis C (200~300 million people are infected with each of the virus worldwide; the two hepatic viral infections are unequally distributed but more concentrated in some regions than others, increasing the chance of dual infection), co-infection of HBV with HCV is common and is associated with an increased morbidity and mortality; as such, HBV vaccination is required to prevent HBV super-infection in HCV-infected individuals. However, HBV vaccine responses in this setting are often blunted, with only ~50% seroconversion (Anti-HBs > 10 IU/ml) compared to >90% in age-matched healthy subjects (HS). This poor vaccine response is also observed in HIV-infected subjects and in other immunocompromised hosts, including the elderly. Attempts to improve immunization responses in both infected and aged humans have been unsuccessful, in part due to our poor understanding of the mechanisms that can dampen vaccine responses in these settings. Recently, we and others have found that chronic viral (HIV, HCV) infection is often associated with T cell exhaustion and senescence, as demonstrated by overexpression of exhaustion and aging markers (such as PD-1, Tim-3, KLRG-1, and DUSP-6), and, in particular, accelerated erosion of telomeres - suggesting excessive proliferative pressure or telomeric DNA damage. Telomere integrity is a key feature of linear chromosomes that preserves genome stability and function, whereas telomere erosion is a hallmark of cell aging or senescence that leads to cell dysfunction or apoptosis, therefore telomere repair is essential to life. While the telomere length is maintained in most cases by a telomerase that prolongs telomeric sequences, we found that telomerase activity is intact, whereas ataxia-telangiectasia-mutated (ATM) - a DNA damage repair enzyme - is inhibited, in nave CD4 T cells derived from HCV-infected subjects. How telomeric DNA damage and repair signaling pathways are dysregulated in the context of HBV vaccine response during HCV infection remain largely unknown. In this proposal, we hypothesize that i) telomere loss-mediated T cell aging plays a pivotal role in HBV vaccine failure in HCV-infected individuals; and ii) lack of ATM-dependent telomeric DNA repair accelerates T cell aging and HBV vaccine failure in HCV infection, thus restoring this telomere repair machinery will open new avenues to protect T cells from aging and to maintain immune competency. To test this hypothesis, we will: 1) characterize the role of telomere loss and T cell aging in HBV vaccine failure during HCV infection; 2) define the mechanisms and impact of ATM deficiency on T cell dysregulation during HCV infection. This translational study is significant in that it will provide a working model to explore mechanisms that may be fundamental to diminishing immune (vaccine) responses that are observed in many chronic infectious diseases, including but not limited to HCV. Understanding such mechanisms is critical for developing approaches to improve vaccine efficacy in the setting of immunocompromised conditions, it is thus significant, timely, and relevant to the Veterans as well as public health.